Hodgkin-Huxley analysis of the data suggests that the kinetics of interaction of general anesthetic molecules with the nerve membrane are different from that of the interaction of either local anesthetics or alcohols. In this proposal, we plan to study in detail the changes in peak sodium and steady-state potassium currents, in voltage-clamped squid giant axon induced by various general anesthetics and other neurally active agents at different temperatures. The ability of general anesthetics to block peak sodium and steady- state currents in nerves will be correlated with potency, polarizability, parachor, lipid solubility and other parameters. The effects of the general anesthetic agent on peak sodium and steady-state potassium currents in an active nerve under different conditions of pressure and temperature will provide an excellent test to the critical volume model and the clathrate formation theories of anesthesia. The former predicts higher pressures as antianesthesia and an increase of anesthetic potency with decrease in temperature. Also, the studies designed to investigate the effects of two or more general anesthetics together (which form different types of clathrates) may show synergistic action in the nerves by blocking peak sodium and steady-state potassium currents. In general, these studies will provide valuable data on the molecular mechanisms(s) of anesthetic action on nervous tissues.